The Proteomic Effects of Cardiopoietic Stem Cell Therapy Following Heart Attack

Cardiopoietic stem cells are used in a form of autologous mesenchymal stem cell therapy. Cells are extracted from patient bone marrow, expanded in culture, and provoked into adopting a cardiac lineage, such that they produce daughter cardiac muscle cells. Human trials have shown benefits in heart attack patients, but, as for all such therapies, it is a question as the degree to which signaling versus integration produces these benefits. Is greater regeneration the result of signaling that changes native cell behavior, followed by the death of near all of the transplanted cells, versus integration of a fraction of those transplanted cells and consequent creation of daughter cells to repair and maintain tissue?

Examining the proteomic differences before and after treatment, as is carried out in mice in this paper, doesn't actually say all that much about which mechanism is dominant. Nonetheless, it is an interesting approach to evaluating exactly what is going on under the hood, and one that should probably be more widely applied during the development of stem cell therapies.

Cardiopoiesis leverages natural developmental cues to impart lineage engagement for enhanced cardioreparative outcome. Applied to adult stem cells, recombinant growth factor-induced cardiopoiesis disrupts latent plasticity to prime cardiovasculogenesis while maintaining a proliferative state. Supported by preclinical studies, cardiopoietic stem (CP) cell-based therapy for heart failure is undergoing clinical evaluation. While global readouts of functional and structural safety and efficacy have been the focus of exploration to date, delineation of the molecular impact of CP cells upon the recipient heart has yet to be charted.

Accordingly, proteomic profiling was here applied to characterize cardiac molecular maladaptation to ischemic cardiomyopathy, and delineate the response of diseased hearts to CP cell treatment. To this end, cells were lineage guided from human bone marrow-derived mesenchymal stem cells (MSCs), consistent with clinical trial cell sourcing. Therapeutic application of human CP cells in a xenograft model of ischemic cardiomyopathy enabled whole ventricle evaluation unachievable from clinical trial participants. This integrative approach resolved widespread proteome remodeling within the infarcted tissue, and captured a non-random reversal of these disease-perturbed derangements following stem cell treatment.

Mass spectrometry resolved and quantified 3987 proteins constituting the cardiac proteome. Infarction altered 450 proteins, reduced to 283 by stem cell treatment. Notably, cell therapy non-stochastically reversed a majority of infarction-provoked changes, remediating 85% of disease-affected protein clusters. Pathway and network analysis decoded functional reorganization, distinguished by prioritization of vasculogenesis, cardiac development, organ regeneration, and differentiation. Subproteome restoration nullified adverse ischemic effects, validated by echo-/electro-cardiographic documentation of improved cardiac chamber size, reduced QT prolongation and augmented ejection fraction post-cell therapy. Collectively, cardiopoietic stem cell intervention transitioned infarcted hearts from a cardiomyopathic trajectory towards pre-disease.

Link: https://doi.org/10.1038/s41536-020-0091-6

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